Boosting corticospinal system synaptic plasticity to recover motor functions

An important strategy to promote voluntary movements after motor system injury is to strengthen the connections between the motor cortex and muscles by taking advantage of the plasticity of the corticospinal motor system. Many neuromodulation approaches are directed to activate the spinal cord and peripheral axons to strengthen muscle activation. We discuss in this perspective that, the cortex and spinal cord should be targeted together to enhance cortex-to-muscle function (Amer and Martin, 2022). Among these protocols, we have used epidural intermittent theta burst stimulation (iTBS) of the motor cortex and transspinal direct current stimulation (tsDCS), a non-invasive approach targeting the cervical and rostral thoracic spinal cord (Song et al., 2016; Song and Martin, 2017; Amer et al., 2021; Amer and Martin, 2022; Williams et al., 2022). In a rodent model, we were the first to combine motor cortex iTBS and tsDCS, an approach that shows promise for clinical efficacy and translational potential for corticospinal tract lesion and spinal cord injury (SCI) (Song et al., 2016; Zareen et al., 2018; Figure 1). To move this, and other approaches, forward for translation it is important to understand the underlying mechanisms better. This will help guide the development of new synergistic strategies to boost the power of plasticity, and further, to guide plasticity for functional recovery after injury.

Figure 1: Neuromodulation strategies.(1) Theta burst stimulation targeting motor cortex; (2) transspinal direct current stimulation targeting the spinal cord; (1) + (2) combined stimulation; closed-loop stimulation dependent on behavioral states (3). Created with BioRender.com.

TBS has been used to induce long-term potentiation (LTP) synaptic plasticity for learning and memory in the cerebral cortex and hippocampus. Using transcranial magnetic stimulation in humans, iTBS received Food and Drug Administration approval to treat forms of depression (Suppa et al., 2016). Motor cortex electrical iTBS, applied invasively, or with transcranial magnetic stimulation, can produce LTP within the corticospinal system. iTBS has been used experimentally to treat neuromuscular disorders such as amyotrophic lateral sclerosis and Parkinson’s disease, as well as SCI (Suppa et al., 2016). We recently found that motor cortex epidural iTBS not only induces LTP-like plasticity in the cortex but also at the corticospinal tract-spinal neuron synapse in the cervical spinal cord in healthy rats (Amer et al., 2021). A single block of iTBS produced a short form of LTP of the motor-evoked potential (MEP) (Amer et al., 2021) and is capable of creating short-term enhancement of the spinal neuron postsynaptic response to motor cortex stimulation (Amer et al., 2021). By contrast, multiple blocks of iTBS are needed to induce a longer-term LTP-like effect. We further showed that repeating motor cortex iTBS across days induced axon sprouting and synaptogenesis within the spinal cord, and long-lasting augmented motor output (Amer and Martin, 2022). This long-term effect could be translated clinically to provide durable improvement of motor function after SCI or stroke. In humans, the relationship between changes in MEP amplitude and duration and motor function are apt to be more complex and the effects of multiple iTBS sessions may yield different directional results. Thus, this effect of iTBS needs to be guided, optimized, and after a major injury like SCI, boosted.

Different from the LTP-like synaptic mechanism targeted by iTBS, tsDCS modulates spinal reflexes and evoked and spontaneous cortical motor output (Jankowska, 2017; Song and Martin, 2022; Williams et al., 2022). Although its major action is the spinal cord, it appears to modulate sensorimotor cortex activity, likely by activating ascending spinal pathways (Jankowska, 2017). It has been used for treating SCI and for pain control. The mechanisms underlying tsDCS, including the neuronal targets engaged by tsDCS and the molecular underpinnings, are still unclear. The effects of tsDCS tend to be polarity dependent (Jankowska, 2017); most studies show that cathodal (c)-tsDCS augments muscle activity while the effects of anodal (a)-tsDCS are inconsistent, either suppressing, facilitating, or no effect (Jankowska, 2017; Song and Martin, 2022). These inconsistencies might result from the electrode configuration and/or spinal segment level. Computer simulation could help to better understand the effects of electrical field direction and neuron responses within the spinal cord with direct current stimulation (DCS) (Song et al., 2015; Song and Martin, 2022), but detailed physiological modeling of spinal neurons is incomplete. The electrode montage is critical for producing the intended neuromodulatory effects (Song and Martin, 2017). With a suitable electrode montage design, c-tsDCS can selectively enhance different motor cortex MEPs, possibly based on the rostrocaudal location of the underlying motor pools (Williams et al., 2022).

Changes in motoneuron excitability induced by spinal neuromodulation may reflect membrane polarization in response to the external applied electrical field, as well as through selective or non-selective actions involving different ion channels (Jankowska, 2017). We have recently shown a novel mechanism for tsDCS. Through single motor unit recording with pharmacological blockade of L-type Ca²⁺ channels, we found that tsDCS modulates spinal activity, in part, by differentially acting on the dendrite and soma of motoneurons. c-tsDCS preferentially activates Ca²⁺ channels in the dendrite to produce persistent inward currents, whereas a-tsDCS preferentially depolarizes the soma. This was further verified with computer simulation (Song and Martin, 2022). There are likely multiple mechanisms underlying c-tsDCS: LTP-like mechanisms may be engaged under some conditions, due to Ca²⁺ influx and possible down-stream signaling, while the intrinsic excitability mechanism might be produced more directly by membrane polarization (Jankowska, 2017; Song and Martin, 2022).

With this understanding of the cellular and molecular mechanisms of iTBS and tsDCS, new therapeutic strategies to boost corticospinal system plasticity for promoting function after an injury can be developed. A co-modulation protocol has been used to promote motor function in rats following selective lesions of the corticospinal tract (pyramidal tract lesion) and spinal cord injury (Song et al., 2016; Zareen et al., 2018). We found that MEP enhancement produced by motor cortex iTBS could be further enhanced by c-tsDCS. We leveraged c-tsDCS to target Ca²⁺ conductances to augment motoneuron activity and persistent inward current-like responses (Song and Martin, 2022). These persistent inward current-like responses are part of the normal function of spinal motor circuits and mostly arise from intrinsic homosynaptic plasticity (Blumberger et al., 2021). Thus, to achieve long-term therapeutic effects after SCI, the two forms of modulation can be combined. We recently found that the LTP-like MEP plasticity could be modulated by combining cortical iTBS with cortical excitatory Designer Receptors Exclusively Activated by Designer Drug action in healthy rats (Amer and Martin, 2022). In vivo slice recordings also show that DCS with TBS increases LTP in the hippocampus (Farahani et al., 2021).

c-tsDCS can augment MEP responses, as well as the rate/slope of response recruitment, during a period of motor cortex iTBS (Song et al., 2016). Further, c-tsDCS produces a 5-fold enhancement of motor cortex MEPs in rats with a cervical level (C4) spinal contusion (Zareen et al., 2018). Combined iTBS-tsDCS therapy, applied daily for 10 days, promotes partial functional recovery. Improvement likely reflects, in part, corticospinal tract outgrowth (Song et al., 2016) and synaptogenesis (Amer and Martin, 2022). Thus, accumulating evidence shows that the combination of activity-based strategies could achieve further enhancement of corticospinal modulation.

Open-loop synergistic iTBS-tsDCS co-modulation enhances synaptic strength and produces structural changes in a rodent model (Song et al., 2016), but a greater capacity for plasticity is likely needed to translate into clinical functional recovery in humans after SCI. Open-loop stimulation can only non-selectively modulate the entire system without targeting particular functional circuits. By contrast, rehabilitation training could modulate the activity of specific functional neuronal groups and circuits. When this co-stimulation was combined with subsequent rehabilitation, improvement in skilled locomotion (horizontal ladder walking) returned performance to pre-injury baseline levels (Sharif et al., 2021). Thus, when combining neuromodulation-induced plasticity with behavior/motor training, the plasticity of the involved neurons will be boosted further and could be translated into functional recovery more efficiently than delivering one or the other alone. How to optimize the protocol, such as whether to use behavioral training before, during, or after the neuromodulation, and the particular stimulation parameters, needs further study. As some neurons are activated or fire during specific behavioral states (such as specific phases of the step cycle, heart cycle, or brain oscillations), state-dependent strategies can be achieved through closed-loop approaches. To promote strong LTP-like motor output of a particular circuit, the training/performance state can be temporally associated with tsDCS. These full state-dependent modulation strategies could accelerate motor function recovery after SCI or other neurologic disorders by providing a further plasticity boost. This could be applicable to strengthen synapses between the spinal and peripheral axons or to reduce spasticity.

In conclusion, motor cortical iTBS strengthens the connectivity of corticospinal pathways and promotes axon sprouting, while tsDCS boosts synaptic connection strength within the spinal cord. Strategies from either iTBS or tsDCS are under testing in clinical trials (Clinical Trials Nos. NCT05388539, NCT03249454). Implementing this dual neuromodulation approach with a state-dependent paradigm could shape specific motor circuits, depending on electrode montage and the behavior being reinforced. In the pursuit to achieve stronger motor output after injury, patient safety must be considered, especially when neuromodulation approaches that may strongly enhance excitability are combined. As new technologies rapidly become available, they can be combined and optimized for clinical translation according to the differing conditions of individual patients and their priorities.

Conflicts of interest: There are no conflicts of interest. Editor note: JHM is an Editorial Board member of Neural Regeneration Research. He was blinded from reviewing or making decisions on the manuscript. The article was subject to the journal’s standard procedures, with peer review handled independently of this Editorial Board member and their research groups.

C-Editors: Zhao M, Liu WJ, Qiu Y; T-Editor: Jia Y